Synthesis, Radiochemistry, and Preclinical Assessment of the First GPR39 PET Imaging Agent

GPR39 is a zinc-sensing G protein-coupled receptor with
critical
roles in neurophysiological and metabolic processes across brain,
pancreas, gut, liver, and fat tissues. Activated by extracellular
zinc ions, GPR39 is involved in neurodegenerative diseases including
altered levels in Alzheimer’s disease (AD). Quantifying GPR39
levels in vivo could significantly advance understanding
of its role in various metabolic and disease processes, enabling drug
development and treatment monitoring. Our study reports the synthesis,
radiolabeling, and comprehensive preclinical evaluation of the first
radiotracer for GPR39 imaging: [11C]TMN-OMe. The radiotracer
demonstrated high radiochemical purity, molar activity, and stability
in human serum. In vivo microPET/CT imaging, biodistribution,
and autoradiography analyses confirmed selective binding to GPR39,
with significantly reduced brain uptake in GPR39 knockout and AD mice,
and in blockade conditions. Collectively, these findings support using
[11C]TMN-OMe to quantify GPR39 levels in vivo and define GPR39-based imaging as a novel platform to study mechanistic
changes in neurological disorders.